Reference SummaryBoolbol SK, Cancer Res 1996 Jun 1;56(11):2556-60

Title

Cyclooxygenase-2 overexpression and tumor formation are blocked by sulindac in a murine model of familial adenomatous polyposis.

Authors

Boolbol SK; Dannenberg AJ; Chadburn A; Martucci C; Guo XJ; Ramonetti JT; Abreu-Goris M; Newmark HL; Lipkin ML; DeCosse JJ; Bertagnolli MM

Journal

Cancer Res

Volume

Issue

Year

1996

Pages

2556-60

Abstract

Inducible cyclooxygenase (Cox-2), also known as prostaglandin H synthase 2 (PGH-2) is a key enzyme in the formation of prostaglandins and thromboxanes, Cox-2 is the product of an immediate-early gene that is expressed in response to growth factors, tumor promoters, or cytokines. Overexpression of Cox-2 is associated with both human colon cancers and suppression of apoptosis in cultured epithelial cells, an activity that is reversed by the nonsteroidal anti-inflammatory drug, sulindac sulfide, To address the relationship between Cox-2, apoptosis, and tumor development in vivo, we studied C57BL/6J-Min/+(Min) mice, a strain containing a fully penetrant dominant mutation in the Ape gene, leading to the development of gastrointestinal adenomas by 110 days of age, Min mice were fed AIN-76A chow diet and given sulindac (0.5 +/- 0.1 mg/day) in drinking water, Control Min mice and homozygous C57BL/6J-+/+ normal littermates lacking the Ape mutation (+/+) were fed AIN-76A diet and given tap water to drink, At 110 days of age, all mice were sacrificed, and their intestinal tracts were examined, Control Min mice had 11.9 +/- 7.8 tumors per mouse compared to 0.1 +/- 0.1 tumors for sulindactreated Min mice, As expected, +/+ littermates had no macroscopic tumors. Examination of histologically normal-appearing small bowel from Min animals revealed increased amounts of Cox-2 and prostaglandin E(2) compared to +/+ littermates, Using two different in situ techniques, terminal transferase-mediated dUTP nick end labeling and a direct immunoperoxidase method, Min animals also demonstrated a 27-47% decrease in enterocyte apoptosis compared to +/+ animals, Treatment with sulindac not only inhibited tumor formation but decreased small bowel Cox-2 and prostaglandin E, to baseline and restored normal levels of apoptosis, These data suggest that overexpression of Cox-2 is associated with tumorigenesis in the gastrointestinal epithelium, and that both are inhibited by sulindac administration.

Links

J:33982 – MGI References
8653697 – National Library of Medicine/PubMed

Strain Notes

Strain	Note
C57BL/6J	Wild type mice on C57BL/6J background. Littermate controls for Apc^Min/+ mice, purchased from The Jackson Laboratory (TJL Stock Number 2020).
C57BL/6J-Apc^Min/+	Cox-2 and Prostaglandin-E2 protein in normal mucosa of the small intestine is elevated in Apc mice as compared to wild type controls. Sulindac dose (160ppm) was ~40% of maximum tolerated dose. These mice were from The Jackson Laboratory.

Models
Strain	Model Name	Treatment Agent(s)	Organ Affected	Frequency
C57BL/6J	Intestine - Large Intestine - Colon tumor		Intestine - Large Intestine - Colon	0
C57BL/6J-Apc^Min/+	Intestine - Large Intestine adenoma	sulindac	Intestine - Large Intestine	10
C57BL/6J-Apc^Min/+	Intestine - Large Intestine tumor		Intestine - Large Intestine	observed
C57BL/6J-Apc^Min/+	Intestine - Small Intestine - Duodenum tumor	sulindac	Intestine - Small Intestine - Duodenum	0
C57BL/6J	Intestine - Small Intestine - Duodenum tumor		Intestine - Small Intestine - Duodenum	0
C57BL/6J-Apc^Min/+	Intestine - Small Intestine - Duodenum tumor		Intestine - Small Intestine - Duodenum	observed
C57BL/6J-Apc^Min/+	Intestine - Small Intestine - Ileum tumor		Intestine - Small Intestine - Ileum	observed
C57BL/6J-Apc^Min/+	Intestine - Small Intestine - Ileum tumor	sulindac	Intestine - Small Intestine - Ileum	0
C57BL/6J	Intestine - Small Intestine - Ileum tumor		Intestine - Small Intestine - Ileum	0
C57BL/6J-Apc^Min/+	Intestine - Small Intestine - Jejunum tumor		Intestine - Small Intestine - Jejunum	observed
C57BL/6J-Apc^Min/+	Intestine - Small Intestine - Jejunum tumor	sulindac	Intestine - Small Intestine - Jejunum	0
C57BL/6J	Intestine - Small Intestine - Jejunum tumor		Intestine - Small Intestine - Jejunum	0
C57BL/6J-Apc^Min/+	Intestine adenoma		Intestine	0
C57BL/6J-Apc^Min/+	Intestine tumor		Intestine	observed
C57BL/6J-Apc^Min/+	Intestine tumor	sulindac	Intestine	10